1. ¹Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, Bizkaia, Spain
2. ²Department of Nursing, University of the Basque Country, Bilbao, Spain
3. ³CIC Biogune Research Center, Derio, Bizkaia, Spain
4. ⁴Barbara Davis Center for Childhood Diabetes, Aurora, CO, USA
5. ⁵Department of Pediatrics, University of the Basque Country, Bilbao, Spain
6. ⁶Department of Medicine, University of the Basque Country, Bilbao, Spain
7. ⁷The Children's Hospital Oakland Research Institute, Oakland, CA, USA
8. ⁸The CBR Institute for Biomedical Research, Boston, MA, USA

Correspondence: Dr L Castaño, Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo, E48903 Bizkaia, Spain. E-mail: lcastano@hcru.osakidetza.net

⁹These authors have equally contributed to this work.

Received 17 April 2006; Revised 15 June 2006; Accepted 21 June 2006; Published online 24 August 2006.

Abstract

The major susceptibility locus for type 1 diabetes mellitus (T1D) maps to the human lymphocyte antigen (HLA) class II region in the major histocompatibility complex on chromosome 6p21. In southern European populations, like the Basques, the greatest risk to T1D is associated with DR3 homo- and heterozygosity and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD) is another DR3-associated autoimmune disorder showing certain overlap with T1D that has been explained by the involvement of common genetic determinants, a situation more frequent in DR3-rich populations, like the Basques. As both T1D- and CD-associated HLA alleles are part of conserved extended haplotypes (CEH), we compared DR3-homozygous T1D and CD patients to determine whether CEHs were equally distributed between both disorders or there was a differential contribution of different haplotypes. We observed a very pronounced distribution bias (P<10^-5) of the two major DR3 CEHs, with DR3-B18 predominating in T1D and DR3-B8 in CD. Additionally, high-density single nucleotide polymorphism (SNP) analysis of the complete CEH [A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202] revealed extraordinary conservation throughout the 4.9 Mbp analyzed supporting the existence of additional diabetogenic variants (other than HLA-DRB1*0301-DQB1*0201), conserved within the DR3-B18 CEH (but not in other DR3 haplotypes) that could explain its enhanced diabetogenicity.